LiverTox: Clinical and Research Information on Drug-Induced Liver Injury

The fluoroquinolones are a family of broad spectrum, systemic antibacterial agents that have been used widely as therapy of respiratory and urinary tract infections. Fluoroquinolones are active against a wide range of aerobic gram-positive and gram-negative organisms. Gram-positive coverage includes penicillinase- and non-penicillinase producing Staphylococci, Streptococcus pneumoniae and viridans, Enterococcus faecalis, Listeria monocytogenes, and Nocardia species. Gram negative coverage includes Neisseria meningitides and gonorrhoeae, Haemophilus influenzae, and most clinically important Enterobacteriaceae species, Pseudomonas aeruginosa and Vibrio species. The fluoroquinolones are believed to act by inhibition of type II DNA toposiomerases (gyrases) that are required for synthesis of bacterial mRNAs (transcription) and DNA replication. They demonstrate little inhibition of human, host enzymes and have had an excellent safety record. The fluoroquinolones are indicated for treatment of several bacterial infections, including bacterial bronchitis, pneumonia, sinusitis, urinary tract infections, septicemia and intraabdominal infections, joint and bone infections, soft tissue and skin infections, typhoid fever, bacterial gastroenteritis, urethral and gynecological infections, and pelvic inflammatory disease and several other infectious conditions. The fluoroquinolones currently available in the United States include ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, norfloxacin, and ofloxacin. These agents are well absorbed orally and well tolerated with a low rate of adverse effects. Several quinolones and fluoroquinolones were introduced, but were subsequently withdrawn after spontaneous reports of severe adverse events including hepatotoxicity: temafloxacin (1992), gatifloxacin (2006), and trovafloxacin (1999). The currently available fluoroquinolones appear to cause idiosyncratic liver injury rarely, at an estimated rate of 1:100,000 persons-exposed. Idiosyncratic liver injury due to fluoroquinolones may be a “class” effect; the pattern of injury is similar, marked by acute and often severe hepatocellular pattern of injury arising within 1 to 4 weeks of starting therapy. The fluoroquinolones most frequently linked to liver injury are ciprofloxacin and levofloxacin, but these two agents also have been most widely used. Minor elevations in liver enzymes occur in 1% to 3% of patients receiving ciprofloxacin, norfloxacin or ofloxacin. Rates with levofloxacin and moxifloxacin are less well defined, but probably similar. The common side effects of the fluoroquinolones are gastrointestinal disturbances, headaches, skin rash and allergic reactions. Less common but more severe side effects include QT prolongation, seizures, hallucinations, tendon rupture, angioedema and photosensitivity. Ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, norfloxacin, and ofloxacin are discussed separately with individual clinical cases and references. General references and selected publications on fluoroquinolones no longer in use are given below.